The past several years have seen a tremendous expansion in the field of stem cell biology. Numerous advances have occurred in understanding the biological relevance of stem cells, as well as their specific molecular properties. An important part of this new era in stem cell science relates directly to hematologic malignancies. Recent studies have led to the identification of a leukemic stem cell (LSC) population in patients with acute myelogenous leukemia (AML). LSCs are sufficient to perpetuate human leukemic cell growth in long-term culture assays and in the murine NOD/SClD model system. As a consequence of these data, it has been proposed that LSCs are central to the pathogenesis of human myeloid leukemia in vivo. Therefore, the primary objective of this application is to define novel molecular properties of LSCs and to exploit such properties to induce LSC-specific apoptosis. With this goal in mind, our studies have focused on defining unique characteristics of the LSC population. To date, we have shown that primitive AML cells aberrantly regulate several factors related to control of cell death decisions. Further, we have developed a model system in which primary AML cells are induced to undergo apoptosis, but normal cells are spared. Thus, we hypothesize that by targeting specific molecular events it will be possible to preferentially induce apoptosis in the LSC population. This hypothesis will be examined through experiments designed to: 1) characterize the molecular basis of apoptosis in primary AML cells, 2) expand strategies for preferential induction of LSC apoptosis, and 3) use molecular genetic strategies to define critical apoptosis control genes that function in LSCs. Collectively, these efforts will advance our understanding of basic mechanisms that underlie leukemic transformation and will improve strategies for the preferential ablation of LSCs.